Involvement of Anaphylatoxins in Regulated Cell Death and Tissue Degeneration after Cartilage Trauma

• Applicant: Dr. Jana Riegger-Koch
• Subject Area: Rheumatology ; Cell Biology
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 498498521

Joint injuries are considered as a major risk factor in the development of an early form of osteoarthritis (OA), also called posttraumatic OA (PTOA). Despite profound evidence that innate immunity, and in particular the complement system, might be involved in PTOA-related pathomechanisms, current orthopedic research has not paid much attention to the “side products” of complement activation - anaphylatoxins (AT) C3a and C5a. Lately, we observed AT-mediated cell death of cartilage cells in presence of tumor necrosis factor alpha (TNF), which might be a crucial aspect in PTOA development but had not been described so far. Moreover, release of cartilage-derived components might play an important role in posttraumatic complement modulation and subsequent AT generation. However, only little is known about this highly relevant topic.The central hypothesis behind the proposed project is that AT represent drivers or co-factors which might be involved in further detrimental processes after cartilage trauma, contributing to the pathogenesis of PTOA. The experiments will be mainly performed by means of our well-established ex vivo human cartilage trauma model and will aim on (1) characterization of cellular and matrix-derived complement-regulators, (2) investigation of trauma-induced AT generation and subsequent influence on chondrocyte metabolism as well as (3) elucidation of the underlying mechanisms behind AT-mediated cytotoxicity under inflammatory conditions. Furthermore, the project will include (4) in vivo investigation of AT-related effects using a PTOA mouse model. Overall, unraveling the mechanisms of complement activation and role of AT after cartilage trauma will provide important insights into the underlying cellular and molecular mechanisms of PTOA pathogenesis. This knowledge might support development of efficient pharmacological treatment strategies, attenuating PTOA progression and improving intrinsic repair.

• DFG Programme: Research Grants